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The experience of psychosis in schizophrenia spectrum disorders involves significant distress and functional impairment, contributing to immense social and economic costs. Current gold standard treatment guidelines emphasize the use of antipsychotic medications, though responses to these treatments vary widely, with the potential for detrimental side effects. However, increasing placebo responses in randomized controlled trials since the 1960s complicate the development of new medications. Elevated placebo responses are common in psychiatric populations, including those with psychosis, and are influenced by individual beliefs and prior experiences. Despite extensive research on placebo mechanisms in conditions such as depression and pain, little is known about mechanisms of these effects in psychosis. This narrative review examines the predictors and belief formation processes underlying placebo and nocebo phenomena in psychosis. We discuss features of randomized controlled trials for antipsychotic medications, individual symptom heterogeneity, and contextual factors. Findings related to placebo effects for motivation and cognition-enhancing drugs are also discussed. We then consider the possibility that theories of predictive coding and aberrant salience provide explanation for aspects of both placebo effects and schizophrenia spectrum symptoms. The role of outcome expectations broadly and in the context of reward processing is considered. We conclude with some recommendations for future placebo research in psychosis, emphasizing the diversity of placebo effects, assessment concerns, cultural considerations, and methodological aspects. Future multidisciplinary research is required to further elucidate placebo effects in schizophrenia spectrum disorders.
Negative symptoms in schizophrenia are critical to functional outcomes but remain difficult to assess reliably. The Brief Negative Symptom Scale (BNSS) was developed to address these challenges, though no validation exists in Romanian-speaking populations. To validate the BNSS in a Romanian clinical sample, explore its psychometric properties and compare BNSS-based and PANSS-based classifications of severe negative symptoms. Forty-seven inpatients with schizophrenia were assessed using Romanian versions of the BNSS, PANSS, CDSS and AIMS. Psychometric analyses included internal consistency, inter-rater reliability, factor analysis and correlation-based validity. Two classification schemes, moderate–severe negative symptoms, measured by BNSS (BNSS-MS), and predominant negative symptoms, measured by PANSS (PANSS-PNS), were compared. The BNSS showed excellent internal consistency (α = .94) and inter-rater reliability (ICC = .98). A five-factor structure was confirmed. BNSS total scores correlated strongly with PANSS negative (ρ = .90), but not with positive, depressive, or motor symptoms. Blunted affect emerged as the most prominent subscale. The BNSS-MS group captured more severe cases than PANSS-PNS and showed greater symptom burden and higher distress scores. The Romanian BNSS is valid and sensitive for detecting negative symptoms, outperforming PANSS in identifying clinically significant subgroups.
The term “betel” most accurately refers to the betel pepper (Piper betle). Confusingly, this term is also frequently used to refer to a street drug that often—but not always—includes the betel leaf as a constituent. This linguistic misdirection only intensifies with terms such as “betel nut,” which, in common usage, may refer to this same composite street drug or to a single isolated constituent of that street drug: the nut of the areca palm (Areca catechu), which is otherwise wholly unrelated to the betel pepper. This composite street drug, colloquially referred to as “betel” or “betel nut” or “betel quid,” is one of the most frequently used psychoactive substances in the world. It carries a cultural legacy spanning over 10,000 years and a current user base numbering in the hundreds of millions. Its primary psychoactive constituent is arecoline, a well-established parasympathomimetic agent. Early studies exploring arecoline’s ability to modulate cholinergic signaling pathways and exert therapeutic psychiatric effects on conditions such as Alzheimer’s disease were initially mired by intolerable parasympathetic side effects. Indeed, over the course of its long history, various hints regarding the therapeutic utility of arecoline have been obfuscated by a variety of challenges which have only recently been overcome. Now, developments in psychopharmacology and our growing understanding of neurochemical brain circuitry have unlocked a new mechanism of action by which arecoline-derived medications interact with dopaminergic processes to improve outcomes for schizophrenia patients. One such medication, xanomeline-trospium (Cobenfy), has emerged as the first such agent to receive U.S. Food and Drug Administration (FDA) approval for the treatment of schizophrenia and represents an entirely new class of pro-cholinergic medication within the field of psychiatry. Many in the field believe that this heralds the beginning of a new era of psychopharmacology: the era of muscarinic agonism. This article briefly described the fascinating journey from ancient betel nuts to modern muscarinic therapeutics.
The hypothesized cognitive model of negative symptoms, proposed nearly twenty years ago, is the most prevalent psychological framework for conceptualizing negative symptoms in schizophrenia spectrum disorders (SSDs). The aim of this study was to comprehensively validate the model for the first time, specifically by quantifying the relationships between negative symptom severity and all related dysfunctional beliefs.
Methods
A systematic search was conducted using MEDLINE and PsychINFO, supplemented by manual reviews of reference lists and Google Scholar. Eligible studies were peer-reviewed with data on the direct cross-sectional association between negative symptoms and at least one relevant dysfunctional belief in SSD patients. Screening and data extraction were completed by independent reviewers. Random-effects meta-analyses were performed to pool effect size estimates of z-transformed Pearson’s r correlations. Moderators of these relationships, as well as subset analyses for negative symptom domains and measurement instruments, were also assessed.
Results
Significant effects emerged for the relationships between negative symptoms and defeatist performance beliefs (k = 38, n = 2808), r = 0.23 (95% CI, 0.18–0.27), asocial beliefs (k = 8, n = 578), r = 0.21 (95% CI, 0.12–0.28), low expectancies for success (k = 55, n = 5664), r = −0.21 (95% CI, −0.15 – −0.26), low expectancies for pleasure (k = 5, n = 249), r = −0.19 (95% CI, −0.06 – −0.31), and internalized stigma (k = 81, n = 9766), r = 0.17 (95% CI, 0.12–0.22), but not perception of limited resources (k = 10, n = 463), r = 0.08 (95% CI, −0.13 – 0.27).
Conclusions
This meta-analysis provides support for the cognitive model of negative symptoms. The identification of specific dysfunctional beliefs associated with negative symptoms is essential for the development of precision-based cognitive-behavioral interventions.
Negative symptoms are a key feature of several psychiatric disorders. Difficulty identifying common neurobiological mechanisms that cut across diagnostic boundaries might result from equifinality (i.e., multiple mechanistic pathways to the same clinical profile), both within and across disorders. This study used a data-driven approach to identify unique subgroups of participants with distinct reward processing profiles to determine which profiles predicted negative symptoms.
Methods
Participants were a transdiagnostic sample of youth from a multisite study of psychosis risk, including 110 individuals at clinical high-risk for psychosis (CHR; meeting psychosis-risk syndrome criteria), 88 help-seeking participants who failed to meet CHR criteria and/or who presented with other psychiatric diagnoses, and a reference group of 66 healthy controls. Participants completed clinical interviews and behavioral tasks assessing four reward processing constructs indexed by the RDoC Positive Valence Systems: hedonic reactivity, reinforcement learning, value representation, and effort–cost computation.
Results
k-means cluster analysis of clinical participants identified three subgroups with distinct reward processing profiles, primarily characterized by: a value representation deficit (54%), a generalized reward processing deficit (17%), and a hedonic reactivity deficit (29%). Clusters did not differ in rates of clinical group membership or psychiatric diagnoses. Elevated negative symptoms were only present in the generalized deficit cluster, which also displayed greater functional impairment and higher psychosis conversion probability scores.
Conclusions
Contrary to the equifinality hypothesis, results suggested one global reward processing deficit pathway to negative symptoms independent of diagnostic classification. Assessment of reward processing profiles may have utility for individualized clinical prediction and treatment.
Recent stressful life events (SLE) are a risk factor for psychosis, but limited research has explored how SLEs affect individuals at clinical high risk (CHR) for psychosis. The current study investigated the longitudinal effects of SLEs on functioning and symptom severity in CHR individuals, where we hypothesized CHR would report more SLEs than healthy controls (HC), and SLEs would be associated with poorer outcomes.
Methods
The study used longitudinal data from the EU-GEI High Risk study. Data from 331 CHR participants were analyzed to examine the effects of SLEs on changes in functioning, positive and negative symptoms over a 2-year follow-up. We compared the prevalence of SLEs between CHR and HCs, and between CHR who did (CHR-T) and did not (CHR-NT) transition to psychosis.
Results
CHR reported 1.44 more SLEs than HC (p < 0.001), but there was no difference in SLEs between CHR-T and CHR-NT at baseline. Recent SLEs were associated with poorer functioning and more severe positive and negative symptoms in CHR individuals (all p < 0.01) but did not reveal a significant interaction with time.
Conclusions
CHR individuals who had experienced recent SLEs exhibited poorer functioning and more severe symptoms. However, as the interaction between SLEs and time was not significant, this suggests SLEs did not contribute to a worsening of symptoms and functioning over the study period. SLEs could be a key risk factor to becoming CHR for psychosis, however further work is required to inform when early intervention strategies mitigating against the effects of stress are most effective.
Executive control over low-level information processing is impaired proximal to psychosis onset with evidence of recovery over the first year of illness. However, previous studies demonstrating diminished perceptual modulation via attention are complicated by simultaneously impaired perceptual responses. The present study examined the early auditory gamma-band response (EAGBR), a marker of early cortical processing that appears preserved in first-episode psychosis (FEP), and its modulation by attention in a longitudinal FEP sample.
Methods
Magnetoencephalography was recorded from 25 FEP and 32 healthy controls (HC) during active and passive listening conditions in an auditory oddball task at baseline and follow-up (4–12 months) sessions. EAGBR inter-trial phase coherence (ITPC) and evoked power were measured from responses to standard tones. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS).
Results
There was no group difference in EAGBR power or ITPC. While EAGBR ITPC increased with attention in HC, this modulation was impaired among FEP. Diminished EAGBR modulation in FEP persisted at longitudinal follow-up. However, among FEP, recovery of EAGBR modulation was associated with reduced PANSS negative scores.
Conclusion
FEP exhibit impaired executive control over the flow of information at the earliest stages of sensory processing within auditory cortex. In contrast to previous work, this deficit was observed despite an intact measure of sensory processing, mitigating potential confounds. Recovery of sensory gain modulation over time was associated with reductions in negative symptoms, highlighting a source of potential resiliency against some of the most debilitating and treatment refractory symptoms in early psychosis.
Schizophrenia is a highly heterogenous disorder with substantial interindividual variation in how the illness is experienced and how it presents clinically. The disorder is composed of primary symptom clusters—positive symptoms, negative symptoms, disorganization, neurocognitive deficits, and social cognitive impairments. These, along with duration, severity, and excluding other possible etiologies, comprise the diagnostic criteria for the disorder outlined in the two commonly used diagnostic classification systems—the Diagnostic Statistical Manual of Mental Disorders, Fifth Edition, Text Revision and the International Classification of Diseases, 11th Revision. These primary symptoms as well as accessory symptoms (mood disturbances, anxiety, violence) and comorbidities (substance use, suicidality) bear upon each other to varying degrees and impact functional outcomes. The following review presents two patient cases illustrating the clinical heterogeneity of schizophrenia, the natural history of the illness and diagnosis, followed by the current understanding of the primary symptom clusters, accessory symptoms, and comorbidities. In addition to noting symptom prevalence, onset, and change over time, attention is paid to the impact of symptoms on functional outcome.
Antipsychotics effective for schizophrenia approved prior to 2024 shared the common mechanism of postsynaptic dopamine D2 receptor antagonism or partial agonism. Positive psychosis symptoms correlate with excessive presynaptic dopamine turnover and release, yet this postsynaptic mechanism improved positive symptoms only in some patients, and with concomitant risk for off-target motor and endocrine adverse effects; moreover, these agents showed no benefit for negative symptoms and cognitive dysfunction. The sole exception was data supporting cariprazine’s superiority to risperidone for negative symptoms. The muscarinic M1/M4 agonist xanomeline was approved in September 2024 and represents the first of a new antipsychotic class. This novel mechanism improves positive symptoms by reducing presynaptic dopamine release. Xanomeline also lacks any D2 receptor affinity and is not associated with motor or endocrine side effects. Of importance, xanomeline treated patients with higher baseline levels of cognitive dysfunction in clinical trials data saw cognitive improvement, a finding likely related to stimulation of muscarinic M1 receptors. Treatment resistance is seen in one-third of schizophrenia patients. These individuals do not have dopamine dysfunction underlying their positive symptoms, and therefore show limited response to antipsychotics that target dopamine neurotransmission. Clozapine remains the only medication with proven efficacy for resistant schizophrenia, and with unique benefits for persistent impulsive aggression and suicidality. New molecules are being studied to address the array of positive, negative and cognitive symptoms of schizophrenia; however, until their approval, clinicians must be familiar with currently available agents and be adept at prescribing clozapine.
The International Classification of Diseases ICD-11 describes a block called ‘Schizophrenia spectrum and other primary psychiatric disorders’ which includes schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder and other specified schizophrenias or other primary psychotic disorders. All these conditions are characterised by impaired assessment of reality and behaviour, delusions, hallucinations, disorganised thinking and behaviour, experiences of passivity and control, negative symptoms, and psychomotor disturbances. The ICD-11 specifies a symptom duration of at least one month and has removed the reliance on Schneiderian first-rank symptoms, giving equal weight to any hallucinations or delusion. Schizophrenia and other psychotic disorders form part of the group of severe mental illness. They can prove difficult to assess and treat in people with intellectual disability. The chapter presents an overview of the condition, the treatments with medication available, and their relevance.
Predominant negative symptoms (PNSs) in schizophrenia can affect the patients’ psychosocial functioning immensely and are less responsive to treatment than positive symptoms.
Aims
The aim of the study was to observe negative symptoms and psychosocial functioning in PNS schizophrenia patients and to understand whether PNS can be improved and with what treatment strategies.
Methods
This was a 1-year, prospective, multicentric cohort study conducted in Slovakia. Adult outpatients with diagnosis of schizophrenia according to ICD-10 and PNS evaluated using the criteria by the European Psychiatric Association’s (EPA) guidance were included. Change in negative symptoms, functionality, and treatment patterns were observed. Treatment effectiveness was evaluated using the modified Short Assessment of Negative Domain (m-SAND), the Self-evaluation of Negative Symptoms (SNS) scale, the Personal and Social Performance (PSP) scale, and the Clinical Global Impression – Severity (CGI-S) and the Clinical Global Impression – Improvement (CGI-I) scales. Least-squares (LS) means were calculated for the change from baseline to final visit for the outcomes.
Results
The study included 188 patients. Functionality improved as, by the end of the study, fewer patients were unemployed (53%) and more worked occasionally (21%). PNS improved significantly according to both physicians and patients (LS mean change from baseline in m-SAND total score: -10.0 (p-value <0.0001)). Most patients received polytherapy throughout the study. Cariprazine was utilized most (20% monotherapy and 76% polytherapy). Only a few patients discontinued treatment due to adverse drug reactions.
Conclusions
With the right treatment strategy, it is possible to achieve improvement in PNS and everyday functioning in schizophrenia outpatients.
Edited by
Andrea Fiorillo, University of Campania “L. Vanvitelli”, Naples,Peter Falkai, Ludwig-Maximilians-Universität München,Philip Gorwood, Sainte-Anne Hospital, Paris
Schizophrenia is a disabling and complex mental disorder that has a negative impact on the real-life functioning of people suffering from this disease, with a consequent huge burden on patients, on their families, and on the healthcare system. Despite the available interventions, only about 15% of subjects with schizophrenia meet the criteria for recovery. This might be due to the fact that available treatments do not satisfactorily target aspects that greatly influence schizophrenia functional outcome, such as negative symptoms and cognitive impairment. Despite the broad consensus on the definition of different negative symptom and cognitive function domains, these aspects are not always assessed in line with current conceptualization, and they are still poorly recognized and often neglected by physicians, family members/caregivers, and the patient himself/herself as they cause much less concern than other clinical features. In this chapter we focus on negative symptoms and cognitive impairment as the two most neglected schizophrenia dimensions in terms of assessment and treatment; we also provide an update of preclinical and clinical research and its relevance to clinical and research practice, and suggest future directions in the field.
Polygenic risk scores for educational attainment (PRSEA), cognitive reserve (CR), and clinical symptoms are associated with functioning in first-episode psychosis (FEP). Nevertheless, the mechanisms underlying their complex interaction are yet to be explored. This study assessed the mediating role of CR and clinical symptoms, both negative (NS) and positive (PS), on the interrelationship between PRSEA and functionality, one year after a FEP.
Methods
A total of 162 FEP patients underwent clinical, functional, and genetic assessments. Using genome-wide association study summary results, PRSEA were constructed for each individual. Two mediation models were performed. The parallel mediation model explored the relationship of PRSEA with functionality through CR and clinical symptoms. The serial mediation model tested a causal chain of the three mediators: CR, NS, and PS. Mediation analysis was performed using the PROCESS function V.4.1 in SPSS V.22.
Results
A serial mediation model revealed a causal chain for PRSEA > CR > NS > Functionality (β = −0.35, 95%CI [−0.85, −0.04], p < 0.05). The model fit the data satisfactorily (CFI = 1.00; RMSEA = 0.00; SRMR = 7.2 × 10−7). Conversely, no parallel mediation was found between the three mediators, PRSEA and functionality and the model poorly fit the data (CFI = 0.30; RMSEA = 0.25; SRMR = 0.11).
Conclusions
Both CR and NS mediate the relationship between PRSEA and functionality at one-year follow-up, using serial mediation analysis. This may be relevant for prevention and personalized early intervention to reduce illness impact and improve functional outcomes in FEP patients.
The conceptualization of negative symptoms (NS) in schizophrenia is still controversial. Recent confirmatory factor-analytic studies suggested that the bi-dimensional model (motivational deficit [MAP] and expressive deficit [EXP]) may not capture the complexity of NS structure, which could be better defined by a five-factor (five NS domains) or a hierarchical model (five NS domains as first-order factors, and MAP and EXP, as second-order factors). A validation of these models is needed to define the structure of NS. To evaluate the validity and temporal stability of the five-factor or the hierarchical structure of the brief negative symptom scale (BNSS) in individuals with schizophrenia (SCZ), exploring associations between these models with cognition, social cognition, functional capacity, and functioning at baseline and at 4 years follow-up.
Methods
Clinical variables were assessed using state-of-the-art tools in 612 SCZ at two-time points. The validity of the five-factor and the hierarchical models was analyzed through structural equation models.
Results
The two models had both a good fit and showed a similar pattern of associations with external validators at the two-time points, with minor variations. The five-factor solution had a slightly better fit. The associations with external validators favored the five-factor structure.
Conclusions
Our findings suggest that both five-factor and hierarchical models provide a valid conceptualization of NS in relation to external variables and that five-factor solution provides the best balance between parsimony and granularity to summarize the BNSS structure. This finding has important implications for the study of pathophysiological mechanisms and the development of new treatments.
Negative symptoms remain poorly understood and treated despite their huge impact on patients’ lives and clinical outcomes. This is partly because of ongoing debates about the clinical constructs underlying negative symptoms. A longitudinal analysis of the structure of negative symptoms presented in BJPsych Open reports striking temporal stability of symptom structure, which behaves as a few independent domains. This further underscores the need to address specific symptom domains when considering interventions or pathophysiology studies.
The structure of negative symptoms of schizophrenia is still a matter of controversy. Although a two-dimensional model (comprising the expressive deficit dimension and the motivation and pleasure dimension) has gained a large consensus, it has been questioned by recent investigations.
Aims
To investigate the latent structure of negative symptoms and its stability over time in people with schizophrenia using network analysis.
Method
Negative symptoms were assessed in 612 people with schizophrenia using the Brief Negative Symptom Scale (BNSS) at baseline and at 4-year follow-up. A network invariance analysis was conducted to investigate changes in the network structure and strength of connections between the two time points.
Results
The network analysis carried out at baseline and follow-up, supported by community detection analysis, indicated that the BNSS's items aggregate to form four or five distinct domains (avolition/asociality, anhedonia, blunted affect and alogia). The network invariance test indicated that the network structure remained unchanged over time (network invariance test score 0.13; P = 0.169), although its overall strength decreased (6.28 at baseline, 5.79 at follow-up; global strength invariance test score 0.48; P = 0.016).
Conclusions
The results lend support to a four- or five-factor model of negative symptoms and indicate overall stability over time. These data have implications for the study of pathophysiological mechanisms and the development of targeted treatments for negative symptoms.
Childhood trauma may impact the course of schizophrenia spectrum disorders (SSD), specifically in relation to the increased severity of depressive or negative symptoms. The type and impact of trauma may differ between sexes. In a large sample of recent-onset patients, we investigated the associations of depressive and negative symptoms with childhood trauma and whether these are sex-specific.
Methods
A total of 187 first-episode psychosis patients in remission (Handling Antipsychotic Medication: Long-term Evaluation of Targeted Treatment study) and 115 recent-onset SSD patients (Simvastatin study) were included in this cross-sectional study (men: n = 218; women: n = 84). Total trauma score and trauma subtypes were assessed using the Childhood Trauma Questionnaire Short Form; depressive and negative symptoms were rated using the Positive And Negative Symptoms Scale. Sex-specific regression analyses were performed.
Results
Women reported higher rates of sexual abuse than men (23.5% v. 7.8%). Depressive symptoms were associated with total trauma scores and emotional abuse ratings in men (β: 0.219–0.295; p ≤ 0.001). In women, depressive symptoms were associated with sexual abuse ratings (β: 0.271; p = 0.011). Negative symptoms were associated with total trauma score and emotional neglect ratings in men (β: 0.166–0.232; p ≤ 0.001). Negative symptoms in women were not linked to childhood trauma, potentially due to lack of statistical power.
Conclusions
Depressive symptom severity was associated with different types of trauma in men and women with recent-onset SSD. Specifically, in women, depressive symptom severity was associated with childhood sexual abuse, which was reported three times as often as in men. Our results emphasize the importance of sex-specific analyses in SSD research.
Recent research has led to important changes in the concepts and assessment of negative symptoms in schizophrenia. We review current negative symptom concepts and their clinical implications, as well as new methods of assessing these symptoms. These changes hold promise for improving our understanding and treatment of negative symptoms.
Edited by
Deepak Cyril D'Souza, Staff Psychiatrist, VA Connecticut Healthcare System; Professor of Psychiatry, Yale University School of Medicine,David Castle, University of Tasmania, Australia,Sir Robin Murray, Honorary Consultant Psychiatrist, Psychosis Service at the South London and Maudsley NHS Trust; Professor of Psychiatric Research at the Institute of Psychiatry
Converging lines of pre-clinical, epidemiological, and experimental evidence support an association between cannabis, cannabinoid agonists, and psychosis (see Chapters 14 and 15). The earliest anecdotal reports on observations between the use of cannabis and subsequent psychosis have been validated by a rich literature of longitudinal studies and more recently experimental studies in humans using a wide array of subjective, cognitive, and electrophysiological outcomes relevant to psychosis. This chapter provides an overview of the subjective psychotic phenomena associated with cannabis and cannabinoids and expands on more objective cognitive and psychophysiological cannabis-related effects pertinent to psychosis.
Important developments in the conceptualisation and classification of negative symptoms have contributed to refining hypotheses on their pathophysiology. The uptake of recent progress is still only partial and the whole field might make a leap forward once relevant studies fully make use of assessment tools based on current conceptualisations.